Overcoming a synthetic obstacle for testing HIV drugs

Over 33 million people are currently living with HIV, and millions will lose their lives to AIDS this year. Thus, there is a sense of urgency in the scientific community when it comes to combatting HIV. One of the most effective treatments so far is HAART (highly active antiretroviral therapy), which drops HIV-1, the more transmittable and virulent virus, in the plasma of patients to undetectable levels. Although a successful therapy, HAART leaves behind small, hidden reservoirs of HIV-1. Current drugs cannot target these latent virus populations, so patients experience viral rebound unless they continuously undergo HAART. By the latest estimate, patients would need decades of uninterrupted treatment to fully remove the latent viral reservoirs. This sort of prolonged period of therapy is likely to have many adverse side effects, ranging from the emergence of drug resistance to increased financial burdens.

One way to avoid chronic drug treatments is to find drugs that work in conjunction with HAART by flushing out the latent virus. Unfortunately, many of the drugs that draw out the virus from reservoirs cause tumors or are toxic in other ways. Two drugs that show promise are prostratin (12-deoxyphorbol-13-acetate) and DPP (12-deoxyphorbol-13-phenylacetate). They do not promote tumors and they can induce HIV expression in latently infected cells.

Unfortunately, further development of prostratin, DPP, or their analogs into therapeutic drugs for clinical trials is quite costly and difficult. The main issue is their availability, since there was no practical synthetic strategy that would create these chemicals in the quantities required for research. Recently, chemists at Stanford solved this problem by publishing an elegant synthesis of prostratin and DPP in Science.

Their synthesis starts with phorbol, which can be isolated from commercially available croton oil. Their synthetic steps have flexibility, allowing additional analogs to be made. The overall yield for their synthesis is 7-16 percent, so it is useful for clinical trials. If these drugs pass clinical trials and are to be made on a large scale for consumers, however, another procedure will be necessary—the synthetic scheme will have to be adapted to fit industrial synthesis, or the cost would be much too high for consumers.

Overall, the researchers produced a functional synthetic strategy that provides easier access to prostratin and DPP for HIV research and increased the range of useful therapeutic agents that can be explored by enabling a variety of analogs to be synthesized. They have also given a valuable starting point for industrial development should these drugs pass clinical trials.

Yun Xie / Yun Xie / Yun Xie is a contributing science writer at Ars, where she covers the latest advancements in science and technology for Ars. She currently works in scientific communications, policy, and review.